CN112250632B - Preparation method of 3,14, 15-triacetyl aconitine - Google Patents
Preparation method of 3,14, 15-triacetyl aconitine Download PDFInfo
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- CN112250632B CN112250632B CN202011291103.XA CN202011291103A CN112250632B CN 112250632 B CN112250632 B CN 112250632B CN 202011291103 A CN202011291103 A CN 202011291103A CN 112250632 B CN112250632 B CN 112250632B
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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Abstract
The invention provides a novel method for preparing 3,14, 15-triacetyl aconitine, which takes aconitine as a raw material, dichloromethane as a solvent and acetic anhydride as an acylating agent to synthesize the 3,14, 15-triacetyl aconitine under the catalysis of 4-dimethylaminopyridine. The 3,14, 15-triacetyl aconitine synthesis process is simple, the problems of low yield, high solvent toxicity and high reaction temperature in the existing method are solved, the purification process is simple, redundant silica gel column chromatography is not needed, and the 3,14, 15-triacetyl aconitine preparation method is beneficial to large-scale industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a method for preparing 3,14, 15-triacetyl aconitine.
Background
Some aconitine substances in the alkaloid have cardiotonic effect, and 3,14, 15-triacetyl aconitine or substances developed by taking the aconitine as an intermediate have the prospect of developing into anti-heart failure medicines.
Document CN110066248 reports a method for preparing 3,14, 15-triacetyl aconitine by acetylation of aconitine as a raw material, which comprises reacting pyridine as a solvent with acetic anhydride, and obtaining 3,14, 15-triacetyl aconitine by a post-treatment method including silica gel column chromatography separation. Experiments show that the method has the defects of incomplete conversion of raw materials, strong volatility and toxicity of the used pyridine solvent, environmental friendliness and relatively high reaction temperature, and simultaneously, the post-treatment and purification by adopting the silica gel column chromatography are not beneficial to scale-up production and high-efficiency industrialization, and the problems of low production efficiency, large consumption of the column-passing solvent, high concentration energy consumption, troublesome operation, more solid wastes and the like are solved.
Disclosure of Invention
The invention aims to provide a preparation method of 3,14, 15-triacetyl aconitine, which has the advantages of simple operation, easy industrialization realization, high yield and environmental protection.
The preparation method comprises the following steps:
a. taking aconitine as a raw material, dichloromethane as a solvent, acetic anhydride as an acylating agent and 4-dimethylamino pyridine as a catalyst, heating and refluxing for reaction, and cooling to room temperature after the reaction is finished;
b. and (b) adding water, sodium carbonate or ammonia water into the solution obtained in the step (a) after the reaction to adjust the pH value, stirring, separating, concentrating the dry organic layer, adding an organic solvent, and recrystallizing to obtain the 3,14, 15-triacetyl aconitine.
Further, the molar ratio of the aconitine to the acetic anhydride is 1 to 5-15, preferably 1.
Further, the molar ratio of the aconitine to the 4-dimethylamino pyridine is 1.
Further, the temperature of the heating reflux reaction in the step a is 30-45 ℃.
Further, the pH value in step b is in the range of 5 to 9, preferably 6.5 to 7.5.
Furthermore, in the step b, the organic solvent is a mixed solvent of ethyl acetate and n-hexane or a mixed solvent of methyl tert-butyl ether and n-hexane, the volume ratio of ethyl acetate to n-hexane is 1.
The invention has the beneficial effects that:
1. the reaction conditions are mild: compared with the synthesis method reported in the patent document CN110066248, the method adopts dichloromethane to replace pyridine as a reaction solvent, so that the temperature of heating and refluxing the reaction is reduced to 40 ℃ from more than 120 ℃, and the reaction condition is mild.
2. More green and environment-friendly: dichloromethane replaces a toxic solvent pyridine to be used as a reaction solvent, and after a catalytic amount of DMAP catalyst is added, the reaction is more environment-friendly.
3. The yield is improved: the yield of the preparation method is obviously improved compared with that reported in patent document CN 110066248.
4. Is beneficial to industrialized mass production: the purification process is simple, complicated silica gel column chromatography is not needed, and purification is only carried out by adopting a recrystallization method, thereby being beneficial to large-scale industrial production.
Detailed Description
The following examples are intended to further illustrate the invention, but are not intended to limit the invention thereto.
Example 1
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 6.6mL (70 mmol) of acetic anhydride and 0.1g (0.9 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of ethyl acetate and 75ml of n-hexane, filtering, and drying to obtain 5.76g of 3,14, 15-triacetyl aconitine, wherein the yield is 92.1%. The reaction steps are as follows:
the product is white amorphous powder, has a molecular formula of C31H47NO12, is easily soluble in methanol, ethanol, pyridine, acetone and dichloromethane, is soluble in ethyl acetate, and is insoluble in n-hexane and water. 1H HMR (400MHZ, CDCl3) delta: 1.12 (3H, t, J =7.2Hz, NCH2 CH3), 2.06 (3H, s, XOAc), 2.07 (3H, s, XOAc), 2.17 (3H, s, XOAc), 3.20 (3H, s, XOCH3), 3.22 (3H, s, XOCH3), 3.27 (3H, s, XOCH3), 3.55 (3H, s, XOCH 3), 4.65 (1H, d, J =5.2Hz, H-14 beta), 4.86 (1H, t, J =8.8Hz, H-3 beta), 5.24 (1H, d, J =6.0Hz, H-15 beta).
13C NMR(100MHZ,CDCl3)δ:13.4(q),20.7(q),21.0(q),31.8(t),32.6(t),40.5(d), 42.0(s),44.5(d),45.5(d),47.4(t),48.9(t),49.5(d),49.5(s),56.1(q),57.7(q),58.6(q), 60.6(d),61.3(q),71.3(d),71.7(t),74.3(s),76.5(s),81.6(d),82.7(d),87.1(d),88.3(d), 170.1(s),170.8(s),173.3(s)。
ESI-MS m/z(％):626.2(100)[M+H+]。
Example 2
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 4.8mL (50 mmol) of acetic anhydride and 0.1g (0.9 mmol) of aconitine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml water and ammonia water to adjust pH =7, stirring, separating, concentrating dry organic layer, recrystallizing with ethyl acetate 15ml and n-hexane 75ml, filtering, and oven drying to obtain 3,14, 15-triacetyl aconitine 5.14g with yield of 82.1%.
Example 3
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 9.5mL (100 mmol) of acetic anhydride, and 0.1g (0.9 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of ethyl acetate and 75ml of n-hexane, filtering, and drying to obtain 5.69g of 3,14, 15-triacetyl aconitine, wherein the yield is 90.9%.
Example 4
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 14.1mL (150 mmol) of acetic anhydride, and 0.1g (0.9 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of ethyl acetate and 75ml of normal hexane, filtering and drying to obtain 5.61g of 3,14, 15-triacetyl aconitine, wherein the yield is 89.7%.
Example 5
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 6.6mL (70 mmol) of acetic anhydride and 0.06g (0.5 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of ethyl acetate and 75ml of n-hexane, filtering, and drying to obtain 5.30g of 3,14, 15-triacetyl aconitine, wherein the yield is 84.7%.
Example 6
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 6.6mL (70 mmol) of acetic anhydride, and 0.02g (0.2 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of methyl tert-butyl ether and 150ml of n-hexane, filtering, and drying to obtain 4.48g of 3,14, 15-triacetyl aconitine, wherein the yield is 71.6%.
Example 7
In a reaction bottle, 5g (10 mmol) of aconitine, 50mL of dichloromethane, 6.6mL (70 mmol) of acetic anhydride and 0g of 4-dimethylaminopyridine are added, and the reaction is finished after heating reflux reaction for 8 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of methyl tert-butyl ether and 150ml of n-hexane, filtering and drying to obtain 3,14, 15-triacetyl aconitine 3.48g, and obtaining the yield of 55.6%.
Example 8
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 6.6mL (70 mmol) of acetic anhydride and 0.24g (2 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of ethyl acetate and 75ml of n-hexane, filtering, and drying to obtain 5.68g of 3,14, 15-triacetyl aconitine, wherein the yield is 90.7%.
Example 9
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 6.6mL (70 mmol) of acetic anhydride, and 0.1g (0.9 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =5, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of ethyl acetate and 75ml of normal hexane, filtering and drying to obtain 5.07g of 3,14, 15-triacetyl aconitine, wherein the yield is 81.0%.
Example 10
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 6.6mL (70 mmol) of acetic anhydride, and 0.1g (0.9 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =9, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of ethyl acetate and 75ml of n-hexane, filtering, and drying to obtain 5.17g of 3,14, 15-triacetyl aconitine, wherein the yield is 82.7%.
Example 11
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 6.6mL (70 mmol) of acetic anhydride and 0.1g (0.9 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of ethyl acetate and 45ml of n-hexane, filtering, and drying to obtain 4.8g of 3,14, 15-triacetyl aconitine, wherein the yield is 76.8%.
Example 12
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 6.6mL (70 mmol) of acetic anhydride, and 0.1g (0.9 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of ethyl acetate and 120ml of normal hexane, filtering and drying to obtain 5.62g of 3,14, 15-triacetyl aconitine, wherein the yield is 89.8%.
Example 13
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 6.6mL (70 mmol) of acetic anhydride and 0.1g (0.9 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of methyl tert-butyl ether and 75ml of n-hexane, filtering, and drying to obtain 5.28g of 3,14, 15-triacetyl aconitine, wherein the yield is 84.4%.
Example 14
In a reaction flask, 5g (10 mmol) of aconitine, 50mL of methylene chloride, 6.6mL (70 mmol) of acetic anhydride and 0.1g (0.9 mmol) of 4-dimethylaminopyridine were added, and the reaction was terminated by heating under reflux for 4 hours. Cooling to room temperature, adding 50ml of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing by using 15ml of methyl tert-butyl ether and 150ml of normal hexane, filtering and drying to obtain 5.48g of 3,14, 15-triacetyl aconitine, wherein the yield is 88.0%.
Claims (1)
1. A preparation method of 3,14, 15-triacetyl aconitine is characterized by comprising the following steps:
adding 5g of aconitine into a reaction bottle, adding 50mL of dichloromethane and 0.1g of acetic anhydride 6.6m L and 4-dimethylamino pyridine, heating and refluxing for 4 hours, cooling to room temperature, adding 50mL of water and ammonia water to adjust the pH to be about =7, stirring, separating, concentrating a dry organic layer, recrystallizing with 15mL of ethyl acetate and 75mL of n-hexane, filtering and drying to obtain 5.76g of 3,14, 15-triacetyl aconitine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110066248A (en) * | 2018-01-24 | 2019-07-30 | 好医生药业集团有限公司 | It is a kind of to prepare the peaceful method of middle crow and its related intermediate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110066248A (en) * | 2018-01-24 | 2019-07-30 | 好医生药业集团有限公司 | It is a kind of to prepare the peaceful method of middle crow and its related intermediate |
| CN110066247A (en) * | 2018-01-24 | 2019-07-30 | 好医生药业集团有限公司 | Middle peaceful crystal form of crow and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| 6β-羟基，乙酰氧基和苯甲酰氧基-3α及β-托品烷衍生物的合成;褚国华等;《药学学报》;19941231;第29卷(第3期);第185-194页 * |
| 利奈唑胺中间体(S)-N-（2-乙酰氧基-3-氯丙基)乙酰胺合成工艺优化;王润南等;《精细石油化工》;20160930;第33卷(第5期);第61-64页 * |
| 泛昔洛韦的合成;陈文华;《化学试剂》;20061231;第28卷(第3期);第185-186，191页 * |
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